Summary A prerequisite for tumor development is acquiring resistance to apoptosis. This can be accomplished through multiple mechanisms, but a frequent alteration in human cancers that protects from apoptosis is the overexpression of one or more of the anti-apoptotic BCL2 family members. BCL2 itself is frequently overexpressed in multiple types of B cell lymphomas and many other lymphoid and non-lymphoid malignancies. Because of the perceived reliance of cancer cells on BCL2 for survival, a targeted specific BCL2 inhibitor was developed, ABT-199 (venetoclax). Although, venetoclax has been FDA approved for the treatment of specific leukemias, clinical trials with venetoclax have not been successful for B cell lymphomas with high levels of BCL2, such as follicular lymphomas and diffuse large B cell lymphomas (DLBCL) that have translocated or amplified BCL2. The results indicate these lymphomas do not require BCL2 for their continued survival, revealing a significant gap in knowledge of what lymphomas use to protect themselves from apoptosis. Recently, we made the unexpected discovery that BCLW, an unexplored anti-apoptotic BCL2 family member that was only thought to be important in spermatogenesis, was overexpressed in six different types of B cell lymphomas, including follicular lymphoma and DLBCL. We determined patients with DLBCL containing higher levels of BCLW had reduced survival, and BCLW was more highly expressed than BCL2 in higher grade follicular lymphoma. We also showed BCLW was necessary for the survival of Burkitt lymphoma cells, and increased levels of BCLW provided resistance to Burkitt lymphoma cells to an inhibitor that targets three anti-apoptotic BCL2 family members. Therefore, we hypothesize BCLW overexpression is necessary for the survival of multiple types of B cell lymphomas and confers resistance to lymphoma cells to venetoclax and other BCL2 family inhibitors. We propose two Aims to test this hypothesis. In Aim 1, we propose to evaluate the requirements of BCLW in multiple different B cell lymphomas in relationship to other BCL2 family members and mechanisms for its overexpression. In Aim 2, we propose to determine the contribution of BCLW to resistance to inhibitors of anti-apoptotic BCL2 family members and ways to overcome this resistance. Completion of these Aims will significantly increase knowledge into the BCL2 family of proteins and the contribution of BCLW to B cell lymphomas and resistance to targeted inhibitors of BCL2 family members. Results are also likely to lead to improved lymphoma clinical trials, diagnostics, prognostics, and therapeutic interventions with knowledge based treatment combinations.